Tracing the evolutions of single-cell 3D genomes in Kras-driven cancers

Although three-dimensional (3D) genome structures are altered in cancer cells, little is known about how these changes evolve and diversify during cancer progression. Leveraging genome-wide chromatin tracing to visualize 3D genome folding directly in tissues, we generated 3D genome cancer atlases of oncogenic Kras-driven murine lung and pancreatic adenocarcinoma. Our data reveal stereotypical, non-monotonic, and stage-specific alterations in 3D genome folding compaction, heterogeneity, and compartmentalization as cancers progress from normal to preinvasive and ultimately to invasive tumors, discovering a potential structural bottleneck in early tumor progression. Remarkably, 3D genome architectures distinguish morphologic cancer states in single cells, despite considerable cell-to-cell heterogeneity. Gene-level analyses of evolutionary changes in 3D genome compartmentalization not only showed that compartment-associated genes are more homogeneously regulated but also elucidated prognostic and dependency genes in lung adenocarcinoma and a previously unappreciated role for polycomb-group protein Rnf2 in 3D genome regulation. Our results demonstrate the utility of mapping the single-cell cancer 3D genome in tissues and illuminate its potential to identify new diagnostic, prognostic, and therapeutic biomarkers in cancer.

尽管癌细胞的三维（3D）基因组结构会发生改变，但目前对这些改变在癌症进展过程中如何演化与多样化的机制仍知之甚少。本研究借助全基因组染色质追踪技术，可直接在组织中可视化三维基因组折叠情况，由此构建了致癌性Kras驱动的小鼠肺腺癌与胰腺腺癌的三维基因组癌症图谱。我们的研究数据显示，随着癌症从正常状态进展至浸润前状态、最终发展为浸润性肿瘤的过程中，三维基因组折叠的压缩程度、异质性以及区室化会呈现出典型、非单调且阶段特异性的改变，并发现了早期肿瘤进展中存在潜在的结构瓶颈。值得注意的是，尽管细胞间存在显著的异质性，但三维基因组架构能够区分单细胞的形态学癌症状态。针对三维基因组区室化演化改变的基因水平分析不仅表明，区室相关基因的调控更为均一，还阐明了肺腺癌中的预后相关基因与依赖基因，以及多梳蛋白Rnf2在三维基因组调控中此前未被重视的作用。本研究结果证实了在组织中绘制单细胞癌症三维基因组图谱的实用性，并阐明了该技术在识别癌症新型诊断、预后及治疗生物标志物方面的潜在价值。